In the past, when administering bioactive peptides or bioactive proteins, oral administration resulted in a poor efficiency of absorption of the drug due to its breakdown by the digestive enzymes in the gastrointestinal tract and enzymes of the intestinal walls, breakdown by intestinal bacteria, absorption by food, etc., and therefore, the general practice had been for administration by injection. Administration by injection, however, is painful to patients and cannot, with some exceptions, be performed by themselves and therefore, a specialist had to be relied on. Therefore, development of a method of administration taking the place of injection has been desired. Active research on new drug delivery systems (DDS) is currently underway and energetic studies are being conducted on oral preparations, rectal preparations, nasal preparations, transdermal preparations, etc. in combination with absorption promoters, but nothing satisfactory has yet come out. In particular, development of new technology is being awaited in administration of hormone-like peptides for which time controlled or intermittent administration is required.
These bioactive peptides are difficult to be absorbed and hard to be absorbed in an effective dosage. Further, since they are amphipathic molecules, when present in an aqueous solution, they are adsorbed on various storage containers and, as a result, are hard to recover from the materials, which is extremely disadvantageous in a small amount of preparations. Accordingly, in the past, containers have been treated with silicone, protein with relatively low adsorption activities compared with these bioactive peptides have been made copresent, or surfactants, hydrocarbons, amino acids, etc. have been blended in so as to try to prevent adsorption on the storage containers (for example, see Japanese Laid-Open Patent Application (Kokai) No. 61-221125 and Japanese Laid-Open Patent Application (Kokai) No. 63-57527).
Iontophoresis is a system for promoting transdermal absorption using electricity. This method of treatment has been known since early 1900. Namely, the molecules having a positive charge pass through the skin layer from the anode side and the molecules having a negative charge pass from the cathode side in an electric field generated through the anode and cathode during conductance of power (J. Controlled Release 18, 213-220, 1992), but recently this technology has been reevaluated as a system for administration of bioactive peptides. Iontophoresis is known to improve the transdermal absorption of peptide type drugs. Much research is going on toward practical application. In iontophoresis, the smaller sized molecules of the peptide easily pass through the skin. Further, steps taken in the preparations to suppress association of the molecules raise the efficiency of permeation through the skin.
As an iontophoretic interface capable of serving as such a drug holding member, an interface having a water-soluble layer, for being impregnated with and holding an ionic liquid drug, comprising a paper material, fabric material, textile material, plastic foam or water-absorbing plastic or other sponge or porous material has been reported. An interface comprising a porous member made of a ceramic etc. or a non-electroconductive material having a porous or capillary construction has also been reported.
There has not, however, been obtained any iontophoretic interface comprising an iontophoretic interface coated with, adhered with, or impregnated with a bioactive peptide or, followed by drying in a solid or sub-dried state which is sufficient in terms of the amount of transdermal absorption and satisfactory in terms of the efficiency of utilization of the drug. The main reason is that these bioactive peptides cannot be used when adsorbed on the drug holding member. As a method to solve this problem, we have already reported a method which coats a non-electroconductive material having a porous or capillary construction with a high molecular weight protein to prevent the adsorption of the drug on the porous material and secure an extremely effective transdermal absorption in a small amount and which is superior in terms of safety as well (see Japanese Laid-Open Patent Application (Kokai) No. 6-16535). This method is extremely effective, but the coating agent used is high priced protein, for example, BSA (bovine serum albumin), which has problems with stability and is troublesome to store over long periods of time. Development of a better method is therefore being sought.
To prevent adsorption of the bioactive peptide on the equipment, as explained above, the method has been reported of adding to the drug-containing solution, for example, benzalkonium chloride or benzethonium chloride etc. in a range of concentration in the solution of 0.1 to 2.0%, but there is the problem with a transdermal drug delivery system using iontophoresis that the target drug ions and the copresent ions electrically compete and, as a result, the rate of transport in the permeation of the drug is lowered, which is a problem from the viewpoint of the objective of raising the efficiency of utilization.
Further, such bioactive peptides are problematic in that, when delivered by transdermal absorption, since the amount used is minute, the drug will be adsorbed at the surface of the skin where it is to be absorbed and accurate control of the dosage into the body will become difficult, and therefore, development of an effective method of preventing adsorption on the skin has been sought for a long time.